There are various uses for silver sulfate, including as a synthetic reagent; a source of silver in the preparation of catalysts, plastic composite materials and various platinum complexes; as well as a source of silver in some photographic processes. Recently silver sulfate has been incorporated into plastics and facial creams as an antimicrobial and antifungal agent. To satisfy the demands of many modern applications, reduction of particle sizes of materials to the micron and nanometer size ranges is often required to take advantage of the higher surface area, surface energy, reactivity, dispersability and uniformity of these size particles; as well as the uniformity and smoothness of coatings made thereof, optical clarity due to reduced light scatter, etc., inherent in these forms of matter. In addition, with the miniaturization of the physical size of many objects and devices, a similar limitation on the physical size of material components is now commonly encountered.
Silver sulfate is a commercially available material that is produced by conventional aqueous precipitation methods. The reaction of equimolar amounts of aqueous solutions of silver nitrate and sulfuric acid to from silver sulfate was described by Th. W. Richards and G. Jones, Z. anorg. Allg. Chem. 55, 72 (1907). A similar precipitation process using sodium sulfate as the source of sulfate ion was reported by O. Honigschmid and R. Sachtleben, Z. anorg. Allg. Chem. 195, 207 (1931). An alternate method employing the immersion of silver metal in a sulfuric acid solution was also reported by O. Honigschmid and R. Sachtleben (loc. cit.). Precipitation of finely divided silver sulfate from an aqueous solution via the addition of alcohol was later reported by H. Hahn and E. Gilbert, Z. anorg. Allg. Chem. 258, 91 (1949). Silver salts are widely known to be thermally and photolytically unstable, discoloring to form brown, gray or black products. Silver ion may be reduced to its metallic state, or oxidized to silver oxide, or react with sulfur to form silver sulfide. Silver sulfate has been observed to decompose by light to a violet color.
The antimicrobial properties of silver have been known for several thousand years. The general pharmacological properties of silver are summarized, e.g., in “Heavy Metals”—by Stewart C. Harvey in The Pharmacological Basis of Therapeutics (Fifth Edition, Chapter 46) by Louis S. Goodman and Alfred Gilman (editors), published by MacMillan Publishing Company, NY, 1975, and “Antiseptics and Disinfectants: Fungicides; Ectoparasiticides”—by Stewart Harvey in The Pharmacological Basis of Therapeutics (Sixth Edition, Chapter 41) by Louis S. Goodman and Alfred Gilman (editors), published by MacMillan Publishing Company, NY, 1980. It is now understood that the affinity of silver ion to biologically important moieties such as sulfhydryl, amino, imidazole, carboxyl and phosphate groups are primarily responsible for its antimicrobial activity.
The attachment of silver ions to one of these reactive groups on a protein results in the precipitation and denaturation of the protein. The extent of the reaction is related to the concentration of silver ions. The diffusion of silver ion into mammalian tissues is self-regulated by its intrinsic preference for binding to proteins through the various biologically important moieties on the proteins, as well as precipitation by the chloride ions in the environment. Thus, the very affinity of silver ion to a large number of biologically important chemical moieties (an affinity which is responsible for its action as a germicidal/biocidal/viricidal/fungicidal/bacteriocidal agent) is also responsible for limiting its systemic action—silver is not easily absorbed by the body. This is a primary reason for the tremendous interest in the use of silver containing species as an antimicrobial, i.e., an agent capable of destroying or inhibiting the growth of microorganisms, such as bacteria, yeast, fungi and algae, as well as viruses. In addition to the affinity of silver ions to biologically relevant species that leads to the denaturation and precipitation of proteins, some silver compounds, those having low ionization or dissolution ability, also function effectively as antiseptics. Distilled water in contact with metallic silver becomes antibacterial even though the dissolved concentration of silver ions is less than 100 ppb. There are numerous mechanistic pathways by which this oligodynamic effect is manifested, i.e., ways in which silver ion interferes with the basic metabolic activities of bacteria at the cellular level to provide a bactericidal and/or bacteriostatic effect.
A detailed review of the oligodynamic effect of silver can be found in “Oligodynamic Metals” by I. B. Romans in Disinfection Sterilization and Preservation, C. A. Lawrence and S. S. Bloek (editors), published by Lea and Fibiger (1968) and “The Oligodynamic Effect of Silver” by A. Goetz, R. L. Tracy and F. S. Harris, Jr. in Silver in Industry, Lawrence Addicks (editor), published by Reinhold Publishing Corporation, 1940. These reviews describe results that demonstrate that silver is effective as an antimicrobial agent towards a wide range of bacteria, and that silver can impact a cell through multiple biochemical pathways, making it difficult for a cell to develop resistance to silver. However, it is also known that the efficacy of silver as an antimicrobial agent depends critically on the chemical and physical identity of the silver source. The silver source can be silver in the form of metal particles of varying sizes, silver as a sparingly soluble material such as silver chloride, silver as a moderately soluble salt such as silver sulfate, silver as a highly soluble salt such as silver nitrate, etc. The efficiency of the silver also depends on i) the molecular identity of the active species—whether it is Ag+ ion or a complex species such as (AgSO4)−, etc., and ii) the mechanism by which the active silver species interacts with the organism, which depends on the type of organism. Mechanisms can include, for example, adsorption to the cell wall which causes tearing; plasmolysis where the silver species penetrates the plasma membrane and binds to it; adsorption followed by the coagulation of the protoplasm; or precipitation of the protoplasmic albumin of the bacterial cell. The antibacterial efficacy of silver is determined, among other factors, by the nature and concentration of the active species, the type of bacteria; the surface area of the bacteria that is available for interaction with the active species, the bacterial concentration, the concentration and/or the surface area of species that could consume the active species and lower its activity, and the mechanisms of deactivation.
Silver sulfate has been proposed as an antimicrobial agent in a number of medical applications. Incorporation of inorganic silver compounds in bone cement to reduce the risk of post-operative infection following the insertion of endoprosthetic orthopedic implants was proposed and studied by J. A. Spadaro et al (Clinical Orthopaedics and Related Research, 143, 266-270, 1979). Silver chloride, silver oxide, silver sulfate and silver phosphate were incorporated in polymethylmethacrylate bone cement at 0.5% concentration and shown to significantly inhibit the bacterial growth of Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. Antimicrobial wound dressings are disclosed in U.S. Pat. No. 4,728,323; wherein a substrate is vapor or sputter coated with an antimicrobially effective film of a silver salt, preferably silver chloride or silver sulfate. Antimicrobial wound dressings are disclosed in WO2006113052A2; wherein aqueous silver sulfate solutions are dried onto a substrate under controlled conditions to an initial color, which is color stable for preferably one week under ambient light and humidity conditions. An antimicrobial fitting for a catheter is disclosed in U.S. Pat. No. 5,049,140; wherein a proposal to fabricate a tubular member composed of a silicone/polyurethane elastomer in which is uniformly dispersed about 1 to 15% wt. of an antimicrobial agent, preferably silver sulfate, is described. A moldable plastic composite comprising cellulose and a urea/formaldehyde resin is disclosed in WO2005080488A1, wherein a silver salt, specifically silver sulfate, is incorporated to provide a surface having antiviral activity against SARS (severe acute respiratory syndrome) corona virus.
A rapidly emerging application for silver based antimicrobial agents is inclusion in polymers used in plastics and synthetic fibers. A variety of methods is known in the art to render antimicrobial properties to a target fiber. The approach of embedding inorganic antimicrobial agents, such as zeolite, into low melting components of a conjugate fiber is described in U.S. Pat. Nos. 4,525,410 and 5,064,599. In another approach, the antimicrobial agent may be delivered during the process of making a synthetic fiber such as those described in U.S. Pat. Nos. 5,180,402, 5,880,044, and 5,888,526, or via a melt extrusion process as described in U.S. Pat. Nos. 6,479,144 and 6,585,843. Alternatively, deposition of antimicrobial metals or metal-containing compounds onto resin film or target fiber has also been described in U.S. Pat. Nos. 6,274,519 and 6,436,420.
In particular, the prior art has disclosed formulations that are useful for highly soluble silver salts having aqueous solubility products, herein referred to as pKsp, of less than 1. In general, these silver salts require the use of hydrophobic addenda to provide the desired combination of antimicrobial behavior and durability. Conversely, it is also known that very insoluble metallic silver particles, having a pKsp greater than 15, would require hydrophilic addenda to provide the desired combination of antimicrobial behavior and durability. There exists a need to provide sparingly soluble silver salts in the range of pKsp from about 3-8, which can be highly efficient in antimicrobial and antiviral behavior when incorporated directly into plastics and polymeric materials.
The use of an organo-sulfate or organo-sulfonate additive as a means of controlling the particle size of precipitated silver sulfate is described in U.S. Pat. No. 7,261,867. Use of an inorganic additive compound that contains a cation capable of forming a sulfate salt that is less soluble than silver sulfate or a halide anion or an oxyanion capable of forming a silver salt that is less soluble than silver sulfate, as a means of controlling the particle size of precipitated silver sulfate is disclosed in U.S. patent application Ser. No. 11/694,582 filed Mar. 30, 2007. However, the inclusion of substantial amounts of organic character in additives to silver sulfate materials has been shown to compromise the thermal stability, resulting in discoloration.
While it is well known that silver-based agents provide excellent antimicrobial properties, aesthetic problems due to discoloration are frequently a concern. This is believed to be due to several root causes, including the inherent thermal and photo-instability of silver ions, along with other mechanisms. A wide range of silver salts are known to be thermally and photolytically unstable, discoloring to form brown, gray or black products. Silver ion may be formally reduced to its metallic state, assuming various physical forms and shapes (particles and filaments), often appearing brown, gray or black in color. Reduced forms of silver that form particles of sizes on the order of the wavelength of visible light may also appear to be pink, orange, yellow, beige and the like due to light scattering effects. Alternatively, silver ion may be formally oxidized to silver peroxide, a gray-black material. In addition, silver ion may simply complex with environmental agents (e.g. grain size controlling agents, polymer additives, catalyst residues, impurities, surface coatings, etc.) to form colored species without undergoing a formal redox process. Silver ion may attach to various groups on proteins present in human skin, resulting in the potentially permanent dark stain condition known as argyria. Silver ion may react with sulfur to form silver sulfide, for which two natural mineral forms, acanthite and argentite, are known to be black in color. Pure silver sulfate (white in color) has been observed to decompose by light to a violet color.
In any given practical situation, a number of mechanisms or root causes may be at work in generating silver-based discoloration, complicating the task of providing a solution to the problem. For example, Coloplast, as describe in U.S. Pat. Nos. 6,468,521 and 6,726,791, disclose the development of a stabilized wound dressing having antibacterial, antiviral and/or antifungal activity characterized in that it comprises silver complexed with a specific amine and is associated with one or more hydrophilic polymers, such that it is stable during radiation sterilization and retains the activity without giving rise to darkening or discoloration of the dressing during storage. Registered as CONTREET™, the dressing product comprises a silver compound complexed specifically with either ethylamine or tri-hydroxymethyl-aminomethane. These specific silver compounds, when used in conjunction with the specific polymer binders carboxymethylcellulose or porcine collagen, are said to have improved resistance to discoloration when exposed to heat, light or radiation sterilization and contact with skin or tissue.
The point in time when discoloration of a composition associated with a silver-based additive appears can range from early in the manufacturing process to late in a finished article's useful life. For example, thermal instability can set in shortly after introduction of the silver-based additive into a high temperature melt-processed polymer, or much later during long-term storage of the material or finished article at lower (e.g. ambient) temperatures, sometimes referred to as long-term heat stability. Likewise, photo-instability can result from short-term exposure to high-energy radiation processing or radiation sterilization, or later from long-term exposure of the material or finished article to ambient light (e.g. requiring ultraviolet (UV) stabilization). In addition, polymeric materials are well known to inherently discolor to some degree either during high temperature melt processing, or later due to aging in the presence of light, oxygen and heat. Thermoplastic polymers such as polyolefins are typically processed at temperatures between about 200-280° C., whereas polyesters are typically processed at higher temperatures between about 240-320° C.
In addition to the color instabilities inherent to silver and to polymeric materials themselves, silver ion imbedded in polymer composites may react with polymer decomposition products (e.g. free radicals, peroxides, hydroperoxides, alcohols, hydrogen atoms and water), modifiers (e.g. chlorinated flame retardants), stabilizers and residual addenda (e.g. titanium tetrachloride, titanium trichloride, trialkylaluminum compounds and the like from Ziegler-Natta catalysts) to form potentially colored byproducts. More particularly, silver ion imbedded in polymer composites may react with grain-size controlling additives and decomposition products formed thereof. Thus the complexity of potential chemical interactions further challenges the modern worker in designing an effective silver-based antimicrobial agent for plastics and polymers while avoiding undesirable discoloration.
A number of approaches have been taken in the past to reduce discoloration resulting from the inclusion of silver-based compounds in melt-processed polymers. Niira et al in U.S. Pat. No. 4,938,955 disclose melt-processed antimicrobial resin compositions comprising a silver containing zeolite and a single stabilizer (discoloration inhibiting agent) selected from the group consisting of a hindered amine (CHIMASSORB™ 944LD or TINUVIN™ 622 LD), a benzotriazole, a hydrazine, or a hindered phenol (specifically octadecyl 3-(3,5-di -tert-butyl-4-hydroxyphenyl)propionate, commercially available as IRGANOX™ 1076). Reduction in long-term discoloration from exposure to 60 days of sunlight in the air was the only response reported.
Ohsumi et al in U.S. Pat. No. 5,405,644 disclose two fiber treatment processes in which the addition of a benzotriazole, preferably methylbenzotriazole, to treatment solutions subsequently inhibits discoloration in fibers comprising a silver containing tetravalent-metal phosphate antimicrobial agent. More specifically, addition of a benzotriazole to an ester spinning oil reduces discoloration in treated fibers following one day exposure to outdoor sunlight; and secondly, the addition of a benzotriazole to an alkali treatment solution reduces discoloration in treated fibers when examined immediately following treatment. It is suggested that the benzotriazole either retards the dissolution of silver ions or inhibits the reaction of small amounts of soluble silver ion with the various chemicals present in the fiber treatment solutions.
Lever in U.S. Pat. No. 6,187,456 discloses reduced yellowing of melt-processed polyolefins containing silver-based antimicrobial agents silver zirconium phosphate or silver zeolite when sodium stearate is replaced with aluminum magnesium hydrotalcite. Tomioka et al in JP08026921 disclose that discoloration from high temperature can be prevented for polypropylene compounded with a silver mixture containing specific amounts of sulfite and thiosulfate ion, if the antimicrobial silver mixture is impregnated on silica gel support. Dispersing silver-based antimicrobial agents into a wax or low molecular weight polymer as a carrier that is intern blended into a higher molecular weight polymer is disclosed in JP03271208A and JP2841115B2 as a safe means to handle higher concentrations of silver-based antimicrobial agents without staining the skin.
Some workers report reducing discoloration by simply combining silver-based antimicrobial agents with other antimicrobial agents in hopes of reducing the total amount of silver in a given formulation. Ota et al in JP04114038 combine silver sulfate with the organic antifungal agent TBZ (2-(4-thiazolyl)benzimidazole) to reduce discoloration in injection molded polypropylene. Herbst in U.S. Pat. No. 6,585,989 combines a silver containing zeolite and the organic antimicrobial agent TRICLOSAN™ (2,4,4′-trichloro-2′-hydroxydiphenyl ether) in polyethylene and polypropylene to yield improved UV stabilization (less yellowness) in accelerated weathering tests. Kimura in U.S. Pat. No. 7,041,723 discloses that for polyolefins containing an antimicrobial combination consisting of (A) a silver containing zeolite and either (B) a silver ion-containing phosphate or (C) a soluble silver ion-containing glass powder, some drawbacks of each antimicrobial agent are mitigated, including the reduction of discoloration from UV light exposure in accelerated weathering tests.
An antimicrobial masterbatch formulation is disclosed in JP 2841115B2 wherein a silver salt and an organic antifungal agent are combined in a low melting wax to form a masterbatch with improved dispersibility and handling safety. More specifically, silver sulfate was sieved through a 100 mesh screen (particles sizes less than about 149 microns), combined with 2-(4-thiazolyl)benzimidazole and kneaded into polyethylene wax. This masterbatch material was then compounded into polypropylene, which was subsequently injection molded into thin test blocks. These test blocks were reported to be acceptable for coloration and thermal stability, while exhibiting antibacterial properties with respect to E. coli and Staphylococcus, and antifungal properties with respect to Aspergillus niger. Similar masterbatches are also described in JP 03271208, wherein a resin discoloration-preventing agent (e.g. UV light absorbent, UV light stabilizer, antioxidant) is also incorporated.
Polymer composites comprising a thermoplastic polymer compounded with a phenolic antioxidant, an organo-disulfide antioxidant, and a silver-based antimicrobial agent, the specified combination of antioxidant stabilizers being superior in inhibiting undesirable discoloration, is disclosed in U.S. patent application Ser. No. 11/669,830 filed Jan. 31, 2007. Alternatively, the use of bromate or iodate ion to inhibit the thermal or light induced discoloration of melt-processed polymers compounded with silver-based antimicrobial agents is disclosed in U.S. patent application Ser. No. 11/694,390 filed Mar. 30, 2007.
Despite various references to the proposed use of silver salts as antimicrobial agents in various fields as referenced above, there are limited descriptions with respect to approaches in the prior art for preparing silver salts, specifically silver sulfate, of sufficiently small grain-size and of optimal grain-size distribution as may be desired for particular applications. A need exists, in particular, to provide antimicrobial agents such as silver salts, more specifically silver sulfate, in controlled particle sizes for use in plastics and polymer containing materials with improved antimicrobial efficacy, reduced cost and reduced discoloration. Toward this end, it is often desirable to reduce the grain size of antimicrobial agents to increase the total surface area, reactivity and dispersability. A further particular need exits to substantially reduce the degree of unwanted discoloration within a plastic or polymer composite and the resultant article containing a silver-based antimicrobial agent with reduced grain-size and/or grain-size distribution resulting from the inclusion of an additive.